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Definitions Gene: A sequence of DNA (a locus on a chromosome) that is involved in (“codes for”) the synthesis of a functional polypeptide (proteins consist of one or more polypeptides, which are strings of amino acids).

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Gene Structure EXON – EX-pressed or coding DNA that is converted into protein INTRON – IN-active or noncoding DNA that is not converted to protein

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Definitions Transcription: One of the two DNA strands is transcribed to a single-stranded nucleic acid called ribonucleic acid (RNA) RNA has the same bases as DNA except uracil (U) substitutes for thymine (T). Translation: Conversion of the basic informational unit of 3 nucleotide bases (called a codon) into a single amino acid.

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Genetic Variation 95% - 98% of human DNA does not code directly for protein. An estimated 99.8% - 99.9% of our DNA is common. But then.1% of 3,000,000,000 = 3 million differences! We are interested in these variations and the transmission and co-aggregation of these variations with AUDs.

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Two major types Microsatellite/short tandem repeat (STR): a stretch of DNA that is sequentially repeated a variable number of times. Can cause disease (e.g. CAG repeat expansion causes Huntington’s disease; Can also be benign variation; Assume it is close to a disease contributing gene;

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Single Nucleotide Polymorphism SNPs are single base pair changes that occur as natural variation in the human genome. They can code for protein change (non- synonymous) or not.

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LINKAGE Basic idea is identity-by-descent (IBD) or how often does an affected pair of relatives share the same ancestral DNA. If more often than expected by chance, then somewhere near this shared DNA is a gene that contributes to affection status. Need related individuals where multiple relatives are affected. Identifies large stretches of DNA.

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Linkage Analysis: The Basics IBD – An Illustration A. One allele IBS and one allele IBD. B. One allele IBS and zero alleles IBD. C. Two alleles IBS and at least one allele IBD.

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LOD score Williams et al., 1999 LOD = Likelihood of Odds; LOD of 3.0 means it is 1000 times more likely than expected by chance that there is linkage. Log 10 1000 = 3 Higher the LOD, more likely genes are nearby

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Problems with Linkage Methodological problems; Need BIG sets of families; Home in on a big chunk of DNA – possibility of hundreds of genes!!! 1 cM (centiMorgan) is approximately equal to 1 Megabase or 1000000 bp!!!! Genes may be anywhere in the 50cM region

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Association Family Based(transmission disequilibrium test) How often is the risk allele transmitted to an affected child from a parent who is heterozygous (A/a) for the SNP? A/a a/a A/a aa a/a A/a A/a A/a a/a A/a

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Many replications… Many studies now show an association between SNPs in GABRA2 and AUDs. SNPs are also associated with drug dependence, nicotine dependence, conduct problems and antisocial personality disorder – likely to be general vulnerability to thrill seeking. Replicated in family-based and case-control studies.

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ADH1B(2)*2  faster to acetaldehyde ADH1C(3)*1  faster to acetaldehyde ALDH2*2  slower breakdown acetaldehyde PROTECTIVE EFFECTS ADH2*2 less common in alcoholics ADH3*1 less common in alcoholics ALDH2*2 less common in alcoholics

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Problems with association studies 1.Population stratification (only when using unrelateds) –when an association between a SNP and AUDs is due to ethnic variation in that SNP. 2.P-values need to be adjusted for testing many markers (e.g. 0.05/#markers tested). 3.Replication in other samples. 4.What does the gene/SNP do in the etiology of AUDs?

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Why study EEG for AUDs? EEG (Electro-encephal0grams) of waves suggest that certain EEG activity is associated with risk for AUDs; EEG is heritable; In families with AUDs, unaffected relatives of AUD individuals have distinct EEG patterns; EEG pattern is not modified when an individual goes into recovery; EEG is an ENDOPHENOTYPE for AUDs

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EEG Waves Alpha waves : major rhythm seen in normal relaxed adults - it is present during most of life especially beyond the thirteenth year when it dominates the resting tracing. Beta activity : dominant rhythm in patients who are alert or anxious or who have their eyes open. Theta activity abnormal in awake adults but is perfectly normal in children upto 13 years and in sleep. Delta activity : quite normal and is the dominant rhythm in infants up to one year and in stages 3 and 4 of sleep. Ref: http://www.brown.edu/Departments/Clinical_Neurosciences/louis/eegfreq.html

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Problems with Endophenotypes Not specific (e.g. P300 amplitude reduction is also associated with schizophrenia); Links between endophenotype and phenotype maybe unknown; Underlying genetic architecture may not be any less complex; Requires special equipment/lab and subject consent;

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Why we are not animals… Animals self administer alcohol and drugs – so do we – but, often, there is a social context for alcohol use in humans. The motivational model of alcohol use is strongly linked to continued drinking. Environmental modified. Rather complex to study in animals.

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WHY DO WE DRINK? Coping motives – How often do you drink to forget your worries? Enhancement Motives – How often do you drink because you like the feeling? Social Motives – How often do you drink to be sociable? Conformity Motives – How often do you drink so you won’t be left out?